Unlocking the biology of the brain is a research imperative that has garnered much attention from public and private entities in recent years. For example, the BRAIN Initiative and EU Initiative (humanbrainproject.eu) are focused on innovative research and technology that increases our understanding of the brain. Neurodegenerative diseases already constitute a public health and economic crisis, and as the population ages, the urgent need for better treatments for these diseases is intensified. With the acquisition of the Covance antibody product portfolio, BioLegend signaled its commitment to enabling legendary discovery within the neuroscience research community. BioLegend is making further investments in the portfolio, becoming a leading provider of reagents known for quality and innovation, and helping scientists advance the understanding of brain biology, interrogate their pathways, and identify potential biomarkers that may improve the success of clinical programs for neurodegenerative diseases.

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01/30/2018

NIH and Michael J. Fox Foundation Announce Partnering Program for Parkinson’s Disease Research

The NIH and the Michael J. Fox Foundation have announced a partnership program along with biopharmaceutical and life science companies that will focus on disease markers for Parkinson’s Disease progression as part of the NIH Accelerating Medicines Partnership (AMP). BioLegend is proud to be a participant and sponsor for the MJFF-led Parkinson’s Progression Markers Initiative (PPMI), which will contribute data and samples for the program. Our LEGEND MAX™ Human α-Synuclein ELISA kit has been used extensively in PPMI’s multi-centered studies for the measurement of α-Synuclein in biological samples.

BioLegend Synaptic Biology Antibody Price Reduction

BioLegend is continually striving to provide top quality reagents to support neuroscience research. Our extensive catalog contains a wide selection of antibodies that recognize targets relevant in Synaptic Biology. We are committed to offering these products at a great value to our customers in an effort to accelerate research and discovery in this area. To this end, we are pleased to announce a permanent price reduction of up to 40% on over 70 targets in this category. Take advantage of this offering and submit a product review from this selection of antibodies to receive a $25 Amazon gift card.

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Alzheimer’s disease is characterized by the accumulation of aggregated Aβ peptides in senile plaques and vascular deposits. Aβ peptides are derived from amyloid precursor proteins (APP) through sequential proteolytic cleavage of APP by β-secretases and γ-secretases generating diverse Aβ species. Aβ can aggregate to form soluble oligomeric species and insoluble fibrillar or amorphous assemblies. Some forms of the aggregated peptides are toxic to neurons.

Alzheimer's disease is characterized by the accumulation of aggregated Aβ peptides in senile plaques and vascular deposits. Aβ peptides are derived from amyloid precursor proteins (APP) through sequential proteolytic cleavage of APP by β-secretases and γ-secretases generating diverse Aβ species. Aβ can aggregate to form soluble oligomeric species and insoluble fibrillar or amorphous assemblies. Some forms of the aggregated peptides are toxic to neurons.

α-synuclein, Alpha-synuclein, is expressed principally in the central nervous system (brain) but is also expressed in low concentrations in a variety of tissues except liver. It is predominantly expressed in the neocortex, hippocampus, substantia nigra, thalamus, and cerebellum of the CNS. It is primarily a neuronal protein, but can also be found in the neuroglial cells. It is concentrated in presynaptic nerve terminals of neurons, as well as having reported nuclear and mitochondrial localization. α-synuclein interacts with plasma membrane phospholipids. α-synuclein in solution is considered to be an intrinsically disordered protein and thus lacks a stable secondary or tertiary structure. However, recent data suggests the presence of partial alpha helical as well as beta sheet structures as well as mostly structured tetrameric states in solution, the equilibrium of which may be altered by binding partners. The human α-synuclein protein is made of 140 amino acids, encoded by the SNCA gene. The primary structure is divided in three distinct domains: (1-60) - An amphipathic N-terminal region dominated by four 11-residue repeats including the consensus sequence KTKEGV. This sequence has a structural alpha helix propensity similar to apolipoproteins-binding domains. (61-95)- a central hydrophobic region which includes the non-amyloid-β component (NAC) region, involved in protein aggregation. (96-140)- a highly acidic and proline-rich region. At least three isoforms of synuclein are produced through alternative splicing. The most common form of the protein, is the full 140 amino acid-long transcript. Other isoforms are alpha-synuclein-126, lacking residues 41-54; and α-synuclein-112, which lacks residues 103-130. α-synuclein may be involved in the regulation of dopamine release and transport and also may function to induce fibrillization of microtubule-associated protein tau. α-synuclein functions as a molecular chaperone in the formation of SNARE complexes. In particular, it can bind to phospholipids of the plasma membrane and to synaptobrevin-2 via its C-terminus domain to influence synaptic activity. α-synuclein is essential for normal development of the cognitive functions and that it significantly interacts with tubulin. It also reduces neuronal responsiveness to various apoptotic stimuli, leading to decreased caspase-3 activation. α-Synuclein fibrils are major substituent of the intracellular Lewy bodies seen in Parkinson's disease.

Glial fibrillary acidic protein is an intermediate filament (IF) protein that is expressed by numerous cell types of the central nervous system (CNS) including astrocytes and ependymal cells. GFAP has also been found to be expressed in glomeruli and peritubular fibroblasts, Leydig cells of the testis, keratinocytes, osteocytes and chondrocytes and stellate cells of the pancreas and liver. GFAP is a type III IF protein that is closely related to its non-epithelial family members, vimentin, desmin, and peripherin, which are all involved in the structure and function of the cell’s cytoskeleton. GFAP is thought to help to maintain astrocyte mechanical strength, as well as the shape of cells.

Type III intermediate filaments are highly conserved and contain three domains, named the head, rod and tail domains. This rod domain coils around that of another filament to form a dimer, with the N-terminal and C-terminal of each filament aligned. Type III filaments such as GFAP are capable of forming both homodimers and heterodimers; GFAP can polymerize with other type III proteins or with neurofilament protein (NF-L). Interestingly, GFAP and other type III IF proteins cannot assemble with keratins, the type I and II intermediate filaments: in cells that express both proteins, two separate intermediate filament networks form.

To form networks, the initial GFAP dimers combine to make staggered tetramers, which are the basic subunits of an intermediate filament. The non-helical head and tail domains are necessary for filament formation. The head and tail regions have greater variability of sequence and structure. In spite of this increased variability, the head of GFAP contains two conserved arginines and an aromatic residue that are required for proper assembly.

Tau proteins are microtubule-associated protein (MAPs) which are abundant in neurons of the central nervous system, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes and elsewhere. One of tau's main functions is to modulate the stability of axonal microtubules. Tau is active primarily in the distal portions of axons providing microtubule stabilization as well as flexibility. Pathologies and dementias of the nervous system such as Alzheimer's disease feature tau proteins that have become defective and no longer stabilize microtubules properly. As a result, tau forms aggregates with specific structural properties referred to as Paired Helical Filaments (PHFs) that are a characteristic of many different types of dementias, known as tauopathies.

Tau has two primary ways of controlling microtubule stability: isoforms and phosphorylation. Six tau isoforms exist in human brain tissue, and they are distinguished by the number of binding domains. Three isoforms have three binding domains and the remaining three have four binding domains. The binding domains are located in the carboxy-terminus of the protein and are positively-charged (for binding to the negatively-charged microtubule). Tau isoforms with four binding domains are better at stabilizing microtubules than those with three binding domains.

Thus, in the human brain, the tau proteins constitute a family of six isoforms with the range from 352-441 amino acids. They also differ in either zero, one or two inserts of 29 amino acids at the N-terminal part (exon 2 and 3), and three or four repeat-binding regions at the C-terminus. So, the longest isoform in the CNS has four repeats (R1, R2, R3 and R4) and two inserts (441 amino acids total), while the shortest isoform has three repeats (R1, R3 and R4) and no insert (352 amino acids total). Tau is also a phosphoprotein with 79 potential Serine (Ser) and Threonine (Thr) phosphorylation sites on the longest tau isoform. Phosphorylation has been reported on approximately 30 of these sites in normal tau proteins. Mechanisms that drive tau lesion formation in the highly prevalent sporadic form of AD are not fully understood, but appear to involve abnormal post-translational modifications (PTMs) that influence tau function, stability, and aggregation propensity.

Microtubules are required for many well characterized functions in eukaryotic cells, including the movement of chromosomes in mitosis and meiosis, intracellular transport, establishment and maintenance of cellular morphology, cell growth, cell migration and morphogenesis in multicellular organisms. Microtubules are associated with a family of proteins called microtubule associated proteins (MAPs), which includes the protein t (tau) and a group of proteins referred to as MAP1, MAP2, MAP3, MAP4 and MAP5. MAP2 is made up of two ~280kDa apparent molecular weight bands referred to as MAP2a and MAP2b. A third lower molecular weight form, usually called MAP2c, corresponds to a pair of protein bands running at ~70kDa on SDS-PAGE gels. All these MAP2 forms are derived from a single gene by alternate transcription.